Digitalis causes several types of cardiac arrhythmias. In Purkinje fibers strophanthidin causes an increase and then a decrease in contractile force. Eventually, fast rhythms develop at the plateau level, which are characterized by small action potentials. The mechanisms by which digitalis induces these electrical and mechanical changes are only imperfectly understood. It has been proposed that the sodium is involved in the onset of arrhythmias while calcium in involved in the therapeutic effects (increase in force of contraction). An excessive calcium appears involved in the toxic mechanical effect (decrease in force). The objective of the proposed research project is to investigate the different mechanisms by which sodium and calcium mediate the electrical and mechanical effect of digitalis and also to correlate these different effects. The microelectrode technique will be used to record membrane potentials and control voltage and a force transducer to measure the force of contraction. Purkinje fibers will be isolated from canine ventricles and perfused in a tissue bath. In different experiments, other cardiac tissues will be used such as the atrial and ventricular muscle fibers and the sinus node. The importance of sodium in the electrical and mechanical effect of strophanthidin will be studied under different conditions which are known to affect sodium influx in different ways. The role of the pump positioning will be assessed by measuring the electrical and mechanical effects of digitalis. The modification of ionic distribution and its effects on the therapeutic and toxic effects will be studied. The influence of voltage on the normal and abnormal currents in the presence of strophanthidin will be assessed. The mechanism of action of local anesthetics and their relation to ion derangements will be tested in the absence and in the presence of strophanthidin. Also, abnormal automaticity as well as abnormal conditions will be subjected to the action of digitalis and of therapeutic agents to find out whether the response is modified. Calcium accumulation will be studied for its relation to the digitalis toxicity.